This invention relates to novel structural and pharmacological analogs of prostacyclin (PGI.sub.2). In particular, the present invention relates to prostacyclin-type compounds wherein the C-5 to C-6 double bond of prostacyclin is isomerized to the C-4 to C-5 position.
Prostacyclin is an endogenously produced compound in mammalian species, being structurally and biosynthetically related to the prostaglandins (PG's ). In particular, prostacyclin exhibits the following structure and atom numbering: ##STR1##
5,6-Dihydroprostacyclin exhibits the following structure and atom numbering: ##STR2##
As is apparent from inspection of formulas I and II, prostacyclin and 5,6-dihydroprostacyclin (i.e., PGI.sub.1) bear a structural relationship to PGF.sub.2 .alpha., which exhibits the following structure and atom numbering: ##STR3##
As is apparent by reference to formula III, prostacyclin and 5,6-dihydroprostacyclin may be trivially named as a derivative of PGF-type compounds. Accordingly, prostacyclin is trivially named 9-deoxy-6,9.alpha.-epoxy-(5Z)-5,6-didehydro-PGF.sub.1 and 5,6-dihydro prostacyclin is named 9-deoxy-6,9.alpha.-epoxy-PGF.sub.1. For description of the geometric stereoisomerism employed above, see Blackwood et al., Journal of the American Chemical Society 90, 509 (1968). Further, for a description of prostacyclin and its structural identification, see Johnson et al., Prostaglandins 12, 915 (1976).
For convenience, the novel prostacyclin analogs described herein will be referred to by the trivial, art-recognized system of nomenclature described by N. A. Nelson, Journal of Medicinal Chemistry, 17, 911 (1974) for the prostaglandins. Accordingly, all of the novel prostacyclin derivatives herein will be named as 9-deoxy-PGF.sub.1 -type compounds or alternatively and preferably as PGI.sub.1 or PGI.sub.2 derivatives.
In the formulas above, as well as in formulas hereinafter, broken line attachments to any ring indicate substituents in "alpha" (.alpha.) configuration i.e., below the plane of such ring. Heavy solid line attachments to any ring indicate substituents in "beta" (.beta.) configuration, i.e., above the plane of such ring. The use of wavy lines (.about.) herein will represent attachment of substituents in either the alpha or beta configuration or attachment in a mixture of alpha and beta configurations.
The side-chain hydroxy at C-15 in the above formulas is in S or R configuration, as determined by the Cahn-Ingold-Prelog sequence rules. See J. Chem. Ed. 41:16 (1964). See also Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins, which discussion applies to the novel prostacyclin analogs herein. Further, the carboxy-terminated side chain is attached to the heterocyclic ring of PGI in either the alpha or beta configuration, which by the above convention represents the (6R) or (6S) configuration, respectively. Expressions such as C-4, C-5, C-6, C-15, and the like, refer to the carbon atom in the prostaglandin or prostacyclin analog which is in the position corresponding to the position of the same number in PGF.sub.2 .alpha. or prostacyclin, as enumerated above.
Molecules of PGI.sub.1, PGI.sub.2, and the novel, asymmetric prostacyclin analogs each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e., the dextrorotatory and levorotatory forms. As drawn, the above formula for PGI.sub.2 corresponds to that endogenously produced in mammalian tissues. In particular, refer to the stereoconfiguration at C-8 (alpha), C-9 (alpha), C-11 (alpha), and C-12 (beta) of endogenously-produced prostacyclin. The mirror image of the above formula for prostacyclin represents the other enantiomer. The racemic forms of prostacyclin contains equal numbers of both enantiomeric molecules, and the above formula I and its mirror image is needed to represent correctly the corresponding racemic prostacyclin.
For convenience hereinafter, use of the term prostaglandin ("PG") or prostacyclin ("PGI.sub.2 ") will mean the optically active form of that prostaglandin or prostacyclin thereby referred to with the same absolute configuration as PGF.sub.2 .alpha., obtained from mammalian tissues.
The term "prostaglandin-type" or "prostacyclin-type" (PG-type or PGI-type) product, as used herein, refers to any monocyclic or bicyclic cyclopentane derivative herein which is useful for at least one of the same pharmacological purposes as the prostaglandins or prostacyclin, respectively.
The formulas as drawn herein, which depict a prostaglandin-type or prostacyclin-type product or an intermediate useful in their respective preparations, each represent the particular steroisomer of the prostaglandin-type or prostacyclin-type product which is of the same relative stereochemical configuration as a corresponding prostaglandin or prostacyclin obtained from mammalian tissues, or the particular stereoisomer of the intermediate which is useful in preparing the above stereoisomer of the prostaglandin-type or prostacyclin-type products.
The term "prostacyclin analog", as used herein, represents that stereoisomer of a prostacyclin-type product which is of the same relative stereochemical configuration as prostacyclin obtained from mammalian tissues or a mixture comprising that stereoisomer and the enantiomer thereof. In particular, where a formula is used to depict a prostacyclin-type product herein, the term "prostacyclin analog" refers to the compound of that formula or a mixture comprising that compound and the enantiomer thereof.
Subsequent to any invention disclosed herein trans-4,5-didehydro-PGI.sub.1 was reported by Nicolaou, et al., J. C. S. Chem. Comm. 1977:331-332 and Corey, et al., JACS 99:2006-2008 (1977).